Phenyltetrahydropyranylpiperazines



United States Patent 3,037,981 PIENILTE'IRAHYDROPYRANYLPIPERAZINES ShinHayao, Elkhart, Ind, assignor to Miles Laboratories, Inc, Elkhart, Ind.,a corporation of lndiana No Drawing. Filed Mar. 23, 1959, Ser. No.800,953 6 Claims. (Cl. 260-268) This invention relates to new and usefulcompositions of matter and particularly tophenyltetrahydropyranylpiperazines which possess physiological activityand are useful as anorexic or appetite-depressant agents in thetreatment of obesity in man.

More specifically, the new compounds may be designated a l-phenyl orl-substituted phenyl-4-(2-tetrahydropyranyl)piperazines and representedby the following structural formula:

wherein R may be hydrogen or halogen atoms or hydroxy, lower alkyl orlower alkoxy groups.

The above defined compounds can be prepared conveniently by reactingphenylpiperazine or an appropriately substituted phenylpiperazine with2-hydroxytetrahydropyran. This mode of formation may be graphicallypresented by the following equations:

EXAMPLE I 1-Phenyl-4-(Z-Tetrahydropyranyl) Piperazine To a solution ofl-phenylpiperazine (32.4 g., 0.2 mole) in 100 ml. of methanol was addedall at once 2-hydroxytetrahydropyran (22.4 g., 0.22 mole) to give aclear solution which in a few minutes separated a crystalline solid. Thereaction mixture was kept at room temperature for 2 hours and the solidwas collected, yield 37.4 g., M.P. 97-98. From the filtrate on additionof water was obtained another 5.4 g. of the product melting at 96-97".

Thus, the total yield of the product was 42.8 g. (87.0%):

A sample was once recrystallized from aqueous methanol to give colorlessneedles melting at 98-99. Analysis.- Calcd. for C H N O: N (basic),5.69. Found: N (basic), 5.66. (Qne N determined by titration.)

The above free base (21.3 g., 0.087 mole) was dissolved in 150 ml. ofhot methanol and added to 100 ml.

3,037,981 Patented June 5, 1962 "ice EXAMPLE [I1-p-Chl0rophenyl-4-(Z-Tetrahydropyranyl)Piperazine To a solution of1-p-chlorophenylpiperazine (78.6 g.,

0.4 mole) in 500 ml. of methanol was added 2-hydroxytetrahydropyran(40.8 g., 0.4 mole) all at once. A colorless solid separated from thesolution in a few minutes. After standing at room temperature for 3hours the solid was collected and dried in air-yield 103.1 g., M.P. 148-148.5. Analysis.Calcd. for C H ClN O: N (basic), 4.99. Found: N (basic),5.05. (One N determined by titration.) The filtrate was diluted withwater to give additional 2.6 g. of the product melting at -146". Thus,the total yield was 105.7 g. (94%). The dihydrochloride did not melt upto 255. Analysis.Calcd. for C15H23C13N2OI N, 7.92. Found: N, 8.00.

EXAMPLE III 1-p-T0lyl-4- (ZTetrahya'ropyranyl)Piperazine This compoundwas prepared in 87% yield from l-ptolylpiperazine andZ-hydroxytetrahydropyran. The pure free base (from aqueous methanol)melted at 93-95. Analysis.Calcd. for C H N O: N, 10.8. Found: N, 10.9. Adihydrochloride was prepared as usual and it melted at 217 (dec.).Analysis.-Calcd. for

HCl, 21.92. Found: HCl, 21.97.

EXAMPLE IV I -p-Methoxyphenyl4- (Z-Tetrahydropyranyl)Piperazine EXAMPLEV 1-o-Chlorophenyl-4-(Z-Tetrahydropyranyl) Piperazine This compound wasprepared in 87% yield from l-ochlorophenylpiperazine and2-hydroxytetrahydropyran. This compound was isolated as amonohydrochloride which melted at 113-114 C. Analysis.Calcd. for C H ClN G: HCl, 11.51. Found: HCl, 11.87.

The novel compounds of this invention, as pointed out above, haveutility as anorexic agents. As such they compare very favorably withcommercially available products in that they surpass them in anorexicactivity. In addition superior utility as appetite-depressantcompositions is indicated at anorexic dosages by the absence of suchundesirable side effects as hypertension, hyperkinesis and CNS.stimulation, which are potentially harmful to patients withcardiovascular disease and which are char acteristic of amphetamines andother anorexic products. This desirable quality in the subject compoundsis attributable to their chemical nature as phenylpiperazine compounds,which as is well known, tend to possess hypotensive properties.

The table below will illustrate in greater detail the anorexic activityof the subject compounds as compared with well known commercialproducts.

. 3 a The data on acute anorexic activity in the rats shown in thistable were obtained by means of a screening technique carried out asfollows: V

Rats are used which have been fasted for18-20 hours, weight 200 g.:50 g.and, without drug, are able to consume one 3 g. food tablet or pelletwithin minutes procedures for preparing a number of representativedosage unit forms of our compositions in accordance with of beingoffered the food. The food test is carried out 45-60 minutes and 165-180minutes after 'iutubations of water (in control experiments) or' afteroral administrationof the drug. Anorexia is assumed for each observa:

tion period if less than 25% of the food offered is not,

consumed.

' COMPARATIVE DATA ON :aANTOREXIC ACTIVITY IN THE 1 Acute mediananorexic dose. 9 Acute median lethal dose for oral adminis ation torats.

The above table clearly demonstrates that, for instance, the subjectcompound of Example II not only approaches d-amphetamine in anorexicactivity but also exhibits a superior duration of anorexic effect,evidenced by the finding that the acute anorexic ED50 at the 3-hourobservation period is identical to that at the 1-hour observationperiod. p 7

Pharmaceutical compositions which have utility as anorexic materials areconveniently and easily produced by combining a compound of the classhereinbefore described with fillers, carriers, extenders and/0rexcipients, such'as are generally used in the preparation ofpharmaceutical products which are to be taken orally or givenparenterally, especially for human use. The .compounds may be used inthe form of the'free base or of the salts of acids which arewater-soluble and non-toxic, such as the hydrochloride, hydrobromide,sulfate and the like. The compositions may be either in solid orliquid'state and may be compounded as tablets, powders, capsules,suspensions and similar dosage forms, particularly useful for oralingestion. In such form the composition may be prepared by mixing theforegoing compounds either in the form of a free base or thewater-soluble non-toxic salts, with such common diluents or tablettingadjuncts as cellulose powder, cornstarch, lactose, talc, stearic acid,magnesium stearate, gums and the like, in accordance with conventionalmanufacturing practices common in the art.

Where the product is to be administered parenterally, the compounds,preferably in the form of their non-toxic water-soluble salts, may beassociated with such carriers as water, saline solution, glucosesolution, and the like.

We have found that for oral administration a suitable dosage unit isfrom about 50 to 300 milligrams of the compound per tablet, capsule, orother dosage form. Where the material is to be administeredparenterally, then a suitable dosage unit would be from about 35 to 300milligrams of the active ingredient.

Dosages as above described may be administered as frequently asconditions demand, and it is understood, of course, that for childrenthe dosages are correspondingly smaller, depending upon the age andWeight of the child, as those skilled in the art will appreciate; a

' The following examples will illustrate in detail typical,

this invention:

EXAMPLE V A pharmaceutical composition having the following formulationwas prepared.

l-p-chlorcphenyl-4-(Z-tetrahydropyranyl)-piperazine 50.0 Lactose 200.0'Magnesiumstearate 5.0

The chlorophenyl-tetrahydropyranylpiperazine is mixed with the lactoseand thoroughly wetted with water. The wetted material is. then pressedthrough a sieve of the desired size and dried in an oven at about 140 F..When dry, the magnesium stearate is added, and the composition isdry-mixed thoroughly. The mixed material is then compressed intotablets.

It will be understood that the above example is only representative ofone specific form of this invention.

Other excipients such as sucrose, sodium chloride, kaolin, dicalciumphosphate and the like may be used. The excipient may be present inamounts varying from about 30 to 300 parts by weight, depending upon thefinal formu- V lation.

Instead of magnesium stearate as the lubricant, stearic acid, boric acidand the like are operable.

For best results from about 2 to 10 parts by weight of the lubricant isused. It will be understood that any of the piperazines described abovemay be used as the aotiveingredient of the composition. Depending on theI dosage unit desired, from 50 to 300 parts of the desired compound willbe used.

EXAMPLE VI For capsules the following formulation was used:

7 Mg. 1ap-chlorophenyl-4-(2-tetrahydropyranyl) -piperazine 500.0 Lactose1000.0 Talc 75.0

This material was prepared as described in Example g V above, that is,the piperazine and the lactose were wetted, sieved, dried, and mixedwith the tale. Capsules each containing 50 mg. of the active ingredientwere prepared.

In summary, the present invention relates to 'l-phenyl or l-substitutedphenyl-4(Z-tetrahydropyranyl)pipera zines which haveiphysiologicalproperties, and to methods of using the same. Formation of the subjectcompounds is eflected by synthesis from a. l-phenyl or l-substitutedphenylpiperazine and 2-hydroxytetrahydropyran. An especially preferredrepresentative compound is'l-p-chlorophenyl-4-(Z-tetrahydropyranyl)piperazine.

For pharmaceutical use the compounds of the present invention may becompounded as tablets, powders, capsules, etc. for oral ingestion,admixed with such common diluents as cornstarch, lactose, talc, etc. orthey may be used together with such carriers as saline or glucosesolutions where to be given parenterally. Suitable dosage units are fromabout 50 to 300 mg. of the compound per tablet or other dosage form fororal administration and from about 25 to 300 mg. for parenteraladministration.

What is claimed is: 1. A new composition of matter selected from thegroup consisting of phenyltetrahydropyranylpiperazines 0 of the formula:

wherein R is a member of the group consisting of hydrogen and halogenatoms and hydroxy, lower alkyl and lower alkoxy groups and non-toxicwater soluble acid addition salts thereof having therapeuticallyacceptable anions.

2. 1-phenyl-4-(2-tetrahydropyranyDpiperazine.

3. 1-p-chloropheny1-4- (2 tetrahydropyranyDpiperazme.

4. l-o-chlorophenyl 4 (2 tetrahydropyranyl)piper-azine.

5. 1-p-tolyl-4-(Z-tetrahydropyranyl)piperazine.

6. 1-p-methoxyphenyl-4-(2 tetrahydropyrany1)piperamm.

References Cited in the file of this patent UNITED STATES PATENTSParcell May 27, 1958 OTHER REFERENCES Cerkovnikov et a1.: Archiv. ZuKenji, pages 28-29 (1946).

Goodwin et al., The Pharmaceutical Jour., vol. 181; 4952, pages 233-235,September 1958.

Laurence et al., British Medical Journal, pages 700-702 (1958).

British Med. 1., pages 938-939, April 19, 1958.

Keele: The Lancet, pages 243-246, Jan. 31, 1959.

1. A MNEW COMPOSISTION OF MATTER SELECTED FROM THE GROUP CONSISTING OFPHENYLTETRAHYDROPYRANYLPIPERAZINES OF THE FORMULA: